Skin Cancer Drug Effective in Mice with Alzheimer’s

Does this mean we should prescribe the drug off-label? Let’s not be hasty.

Although Alzheimer’s disease (AD) develops differently from person to person, many common symptoms exist. In the early stages, the most common symptom is a difficulty remembering recent events. If AD is suspected, it’s usually confirmed with behavioral and memory tests and typically a brain scan. As the disease advances, other symptoms develop such as confusion, irritability, mood swings, speech problems and long-term memory loss. Withdrawal from family and society accompany these symptoms as well. And bodily functions are gradually lost, which ultimately leads to death.

On average, the life expectancy following diagnosis is about seven years. Fewer than 3% live more than 14 years after diagnosis. The cause and progression of Alzheimer’s disease are poorly understood. Recent research suggests that it’s associated with the development of amyloid plaques and neurofibrillary tangles within the brain. Current treatments only help with the symptoms of the disease. At this point, over 1,000 clinical trials have been conducted in order to find ways of treating the disease. Mental stimulation, physical exercise and a balanced diet have been suggested as ways to delay cognitive decline in healthy older individuals, but there’s no conclusive evidence supporting an effect.

Research Shows a Skin Cancer Drug Clears Amyloid Plaques
A dramatic new study offers the first real hope for a treatment. A team of researchers led by Gary Landreth at Case Western Reserve University School of Medicine found that a drug called Bexarotene (TargretinTM) has a remarkable effect on mice with a condition similar to Alzheimer’s in humans. These mice, like humans, have beta-amyloid protein plaques in their brains. They also have behavioral and cognitive impairment similar to those in Alzheimer’s patients. Within hours of administering Bexarotene to mice in Landreth’s, plaques began to clear. And within a few days the mice recovered the cognitive functions they’d lost.

Bexarotene is an orphan drug, approved for use in humans to treat a rare form of skin cancer called cutaneous T-cell lymphoma. The drug exists in a class of medications known as retinoids and works against lymphoma by stopping the growth of cancer cells. In AD models, it’s believed to work by inhibiting a gene called RXR, involved in the production of beta-amyloid proteins. The researchers hypothesized that the rapid, plaque-clearing response occurs because Bexarotene readily crosses the blood-brain barrier. While current medications used in Alzheimer’s disease are aimed at symptom relief, Bexarotene is thought to attack the disease at its underlying pathology. While other treatments targeting beta-amyloid have shown promise in mouse models, they’ve been largely unsuccessful in humans.

Of Mice and Men
A paradigm in science is that many promising drugs that work in animals, fail when used in humans. Bexarotene is somewhat different, in the sense that it’s already approved for human use. However, it hasn’t been formally tested in Alzheimer’s patients. Because Alzheimer’s affects so many people, some have proposed Bexarotene’s immediate “off-label” use in AD patients. However, experts argue that prescribing the drug, while legal, would be unethical.

Dr. James Galvin, an Alzheimer’s specialist at NYU, says, “Off-label use of medications without proper testing may expose patients and their families to serious side effects without the possibility of benefit. Furthermore, he says, “In the absence of any human trials, I believe it’s unethical to prescribe a medication without evidence of efficacy and safety.”

And one shouldn’t forget that Bexarotene is a cancer drug and can cause serious side effects, such as headaches, hair loss, nausea, depression and elevated cholesterol levels. And many elderly patients, especially those with Alzheimer’s take multiple medications, so Bexarotene could interact or interfere with their prescriptions.

The Off-Label Debate: Where do you Stand?
While you consider the ethical quandary, keep in mind that Bexarotene was proven safe in humans and approved by the FDA, albeit for another disease. In spite of the known side effects and possibility of drug interactions, given the profound results in the Case Western study, should those 36 million people now suffering from Alzheimer’s have a choice to take the drug?

Given that drugs which work in animals sometimes don’t have the same effect in humans, it’s probable the leukemia-approved Bexarotene wouldn’t reverse or even slow the decline of those with AD. But with a tragic decline in the quality of life and a life expectancy of seven years, should those who want to brave the off-label unknowns be allowed to do so?

Many cancer patients agree to highly toxic chemotherapeutic treatments in hopes of spending even six more months with their families. Such patients often side-step the ethical debates in favor of any approach that will extend life. Of course, we all fall on different sides of the issue. So the question remains: Should a drug that’s effective in animals against the underlying pathology of Alzheimer’s, but proven safe in humans for leukemia be prescribed off-label?

If I had a loved one with Alzheimer’s Disease that was non-responsive to any medications, I know what I would want to do. What would you do?